In vitro metabolism, disposition, preclinical pharmacokinetics and prediction of human pharmacokinetics of DNDI-VL-2098, a potential oral treatment for Visceral Leishmaniasis

• DOI: 10.1016/j.ejps.2014.09.006
• Publication Date: 2014-09-27T19:32:38Z
• Authors: Rao Mukkavilli; Jakir Pinjari; Bhavesh Patel; Shankar Sengottuv...; Subodh Mondal; Ajit Gadekar; Manas Verma; Jignesh Patel; Lavanya Pothuri; Gopu Chandrashekar; Prabhakar Koiram; Tanukrishnan Hari...; Ansari Moinuddin; Delphine Launay; Nimish Vachharajani; Vikram Ramanathan; Denis Martin
• Keywords: Mesocricetus

The in vitro metabolism and vivo pharmacokinetic (PK) properties of DNDI-VL-2098, a potential oral agent for Visceral Leishmaniasis (VL) were studied used to predict its human pharmacokinetics. DNDI-VL-2098 showed low solubility (10 μM) was highly permeable (>200 nm/s) the Caco-2 model. It stable liver microsomes hepatocytes no metabolite detectable circulating plasma from dosed animals suggesting very slow, if any, compound. moderate bound proteins across species tested (94–98%). satisfactory PK mouse, hamster, rat dog with blood clearance (<15% hepatic flow except hamster), volume distribution about 3 times total body water, acceptable half-life (1–6 h species) good bioavailability (37–100%). Allometric scaling preclinical data gave approximately 20 that compound could be once-a-day drug. Based on above assumptions, minimum efficacious dose predicted 50 kg 150 mg 300 mg, using efficacy results mouse respectively.